DNA is a complex macromolecule whose immunological activities are influenced by its base composition and base modification, as well as helical orientation. Certain unusual DNA structures (e.g., Z-DNA) can induce significant antibody responses when administered to normal mice. In addition, bacterial DNA, as well as certain synthetic ODNs containing unmethylated CpG sequences can induce proliferation and immunoglobulin (Ig) production by murine B cells. Unmethylated CpG dinucleotides are more frequent in the genomes of bacteria and viruses than vertebrates. Recent studies suggest that immune recognition of these motifs may contribute to the host's innate immune response. D. M. Klinman et al., CpG Motifs Present in Bacterial DNA Rapidly Induce Lymphocytes to Secrete Interleukin 6, Interleukin 12, and Interferon γ, 93 Proc. Natl. Acad. Sci. USA 2879 (1996); A.-K. Yi et al., Rapid Immune Activation by CpG Motifs' in Bacterial DNA, 157 J. Immun. 5394 (1996); Hua Liang et al., Activation of Human B Cells by Phosphorothioate Oligodeoxynucleotides, 98 J. Clin. Invest. 1119 (1996); A. M. Krieg et al., CpG Motifs in Bacterial DNA Trigger Direct B-Cell Activation, 374 Nature 546 (1995).
In mice, CpG DNA induces proliferation in almost all (>95%) of B cells and increases Ig secretion. This B-cell activation by CpG DNA is T-cell independent and antigen non-specific. In addition to its direct effects on B cells, CpG DNA also directly activates monocytes, macrophages, and dendritic cells to secrete a variety of cytokines. These cytokines stimulate natural killer (NK) cells to secrete γ-inteferon (IFN-γ) and have increased lytic activity. Examples of which can be found in International Patent Applications WO 95/26204, WO 96/02555, WO 98/11211, WO 98/18810, WO 98/37919, WO 98/40100, WO 98/52581, PCT/US98/047703, and PCT/US99/07335; U.S. Pat. No. 5,663,153; and U.S. patent application Ser. Nos. 08/276,358, 08/386,063, 08/461,036, 08/462/799, 08/960,774, 08/738,652, 09/030,701, 09/082,649, 09/191,170, 09/09/136,138, 09/154,614, and 09/286,098.
Although bacterial DNA and certain ODNs can induce a murine immune response, little is known about the immunostimulatory capacity of these materials for the human immune system. Z. K. Ballas et al., Induction of NK Activity in Murine and Human Cells by CpG Motifs in Oligodeoxynucleotides and Bacterial DNA, 157 J. Immun. 1840 (1996). Differences in the responsiveness of human and murine B cells to certain stimuli render it impossible to extrapolate results obtained from mouse to man.
In view of the above, there exists a need for ODNs that induce an immune response in humans. In addition, there is a need for methods utilizing ODNs in the treatment of human diseases. The present invention provides such ODNs and methods of use. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.